Hippocampal-Hypothalamic Network Mechanisms of Maladaptive Contextual Eating

了解大脑如何支持日常行为是神经科学的一个中心目标，对于设计生物学相关的干预措施，重新平衡异常的神经元活动和消除不适应的行为模式，具有潜在的深远影响。值得注意的是，人类和动物往往会摄入超出新陈代谢和体内平衡需要的食物。在饥饿之前进食和不断探索新的食物是生存和适应的核心行为模式。然而，加剧的非稳态喂养现在是一个主要负担，代表着广泛传播的饮食失调，使个人肥胖，影响他们的家庭，卫生部门和更广泛的英国经济。此外，饮食失调并不是孤立出现的，它通常与包括记忆功能障碍在内的其他疾病一起发生。从代谢和体内平衡的角度对食物摄入的神经生物学进行了广泛的研究，研究确定了下丘脑外侧（LH）中饥饿和饱腹感的神经基质。但是，记忆回路决定我们什么时候吃、吃多少的认知过程仍未被探索。海马体（HPC）是记忆引导行为的核心大脑网络，最近有人认为它也处理与食物有关的信息。然而，神经元底物，编码方案和通路支持这种记忆控制进食行为仍然难以捉摸。因此，在这里，我们试图提供一个大脑网络水平的机制理解记忆激活，非稳态喂养。我们的方法将使用尖端的大脑记录技术结合遗传方法来监测和操纵小鼠HPC和LH区域的细胞活动，这些细胞以空间环境依赖的方式增加他们的食物摄入量。这个项目将涉及三个科学目标。揭示暴饮暴食对海马记忆网络的影响。我们将研究不断升级的高美味食物的情境进食与HPC活动动态之间的关系，HPC活动动态支持记忆，将神经元放电活动的变化与个体消耗食物资源的倾向联系起来。我们将测试三个假设：(i)对食物摄入作出反应的HPC神经元子集提供最后一餐的内部表征；（ii）可口食物的重复喂食经验使HPC网络活动倾向于异常的食物环境细胞组合；（iii）不断升级的情境进食通过增强完善行为期间的神经元同步，诱导不必要的HPC网络可塑性。揭示跨网络hpc - lh活性基序在不断升级的上下文喂养。我们将(i)定义接受直接HPC神经输入的LH神经元的电生理和分子特征；（ii）识别由高语境进食引起的HPC-LH活性变化，包括跨网络HPC-LH细胞组装的计算。3. 操纵沿hpc - lh通路的神经元活动，恢复正常的情境进食。我们将采用最先进的光遗传学干预方法(i)活性依赖性，（ii）细胞类型选择性和（iii）输入定义，以探索沿hpc - lh通路控制活性并取消功能失调喂养的策略。我们的第一个策略是“重新编程”海马体对环境与美味食物配对的表征，使其成为替代的、中性的表征。第二种策略是通过实时检测HPC网络动态来“重新平衡”HPC连接的LH神经元的活动。总的来说，我们的实验将对全面理解升级的、情境依赖的进食行为背后的大脑网络层面机制做出重大贡献。我们的项目将进一步为饮食失调和记忆功能障碍之间高发病率的神经基础提供重要的新见解。

Understanding how the brain supports everyday behaviour is a central goal of neuroscience, with potential far-reaching consequences for designing biologically relevant interventions that rebalance aberrant neuronal activity and cancel maladaptive behavioural patterns.Notably, humans and animals are prone to eat beyond metabolic, homeostatic needs. Eating before being hungry and continually exploring new food items are behavioural patterns central to survival and adaptation. However, exacerbated non-homeostatic feeding is now a major burden, representing a wide spread eating disorder that expose individuals to obesity and affect their families, the health sector and the wider UK economy. Moreover, eating disorders do not develop in isolation and typically occur along with other conditions including dysfunctional memory.The neurobiology of food-intake has been widely investigated from a metabolic and homeostatic perspective, with studies identifying neural substrates of hunger and satiety in the lateral hypothalamus (LH). But the cognitive processes where memory circuits shape when and how much we eat remain unexplored. The hippocampus (HPC) is a brain network central to memory-guided behaviour that has been recently suggested to also process food-related information. However, the neuronal substrates, coding schemes and pathways underpinning such a mnemonic control of feeding behaviour remain elusive. Accordingly, here we seek to deliver a brain network-level mechanistic understanding of memory-invigorated, non-homeostatic feeding.Our approach will use cutting-edge technologies for brain recordings combined with genetic approaches to monitor and manipulate the activity of cells in the HPC and LH regions of mice that escalate their food intake in a spatial context dependent manner. This project will address three scientific objectives.1. To reveal the effect of excessive eating on the hippocampal memory network.We will investigate the relationships between escalated contextual eating of highly palatable food and HPC activity dynamics known to support memory, associating changes in neuronal firing activity with individual's propensity to consume food resources. We will test three hypotheses: (i) a subset of food-intake-responding HPC neurons provides an internal representation of the last meal; (ii) repeated feeding experience of palatable food biases HPC network activity towards aberrant food-context cell assemblies; and (iii) escalated contextual eating induces unwanted HPC network plasticity by enhancing neuronal synchronisation during consummatory behaviour.2. To uncover cross-network HPC-to-LH activity motifs in escalated contextual feeding.We will (i) define the electrophysiological and molecular profiles of LH neurons that receive direct HPC neural inputs; and (ii) identify HPC-to-LH activity changes caused by heightened contextual eating, including the computation of cross-network HPC-LH cell assemblies. 3. To manipulate neuronal activity along the HPC-to-LH pathway and restore normal contextual eating.We will deploy state of the art optogenetic interventions that are (i) activity-dependent, (ii) cell-type-selective, and (iii) input-defined, in order to probe strategies that control activity along the HPC-to-LH pathway and cancel dysfunctional feeding. Our first strategy consists in "reprograming" hippocampal representations of environments paired with palatable food into alternative, neutral representations. The second strategy consists in "rebalancing" the activity of HPC-connected LH neurons using real-time detection of HPC network dynamics.Collectively, our experiments will make a major contribution to a comprehensive understanding of the brain network-level mechanism underlying escalated, context-dependent feeding behaviour. Our project will further provide important new insights into the neuronal foundation of the high co-morbidity between eating disorders and dysfunctional memory.